It Is The N Proteins Of The SARS-CoV-2 Virus That Is Activating The NLRP3 Inflammasome To induce Hyperinflammation And Not The Spike Proteins!

A new study by researchers from various medical and research institutions in China led by scientists from the State Key Laboratory of Virology-Wuhan University has found that it is the N or nucleocapsid proteins of the SARS-CoV-2 coronavirus that is activating the NLRP3 Inflammasomes resulting in hyperinflammation and not the spike proteins.

Typically excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity.
 
The study findings demonstrate a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation.
 
Nucleocapsid or N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice.
 
The findings showed that mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by inhibitors of NLRP3 and inhibitors of caspase-1.
 
The study findings reveal a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.
 
The study findings were published in the peer reviewed journal: Nature Communications. https://www.nature.com/articles/s41467-021-25015-6
 
The fast and extensive spread of the SARS-CoV-2 coronavirus has posed a serious threat to the global health and economy. To date, SARS-CoV-2, which is the virus responsible for the COVID-19 disease, has claimed more than 4.28 million lives worldwide and infected more than 201 million individuals.

The SARS-CoV-2 virus belongs to the family Coronaviridae, and is a highly infectious virus that mainly infects the respiratory tract of humans. The viral genome of SARS-CoV-2 is found within the nucleocapsid (N) protein, which is embedded inside phospholipid bilayers and covered by a spike (S) protein.
 
Besides the N and S proteins, SARS-CoV-2 has two other two structural proteins including the membrane (M) and envelope (E) proteins, both of which are located in the viral envelope. SARS-CoV-2 also encodes for several accessory proteins.
 
Typically SARS-CoV-2 infections can cause a wide range of symptoms ranging from mild to severe, the latter of which can result in serious complications and sometimes death. Scientists believe that in order to contain the spread of SARS-CoV-2, it is essential to understand the pathogenesis of this virus.
 
It has also been found that severe inflammatory responses often occur when SARS-CoV-2 infects the human respiratory tract.
 
Past research has shown that a dysregulated innate immune response is associated with the clinical symptoms of severe COVID-19 inf ections. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191310/
 
Unknown to many, Inflammasomes are cytosolic multiprotein oligomers of the innate immune system that are responsible for the activation of inflammatory responses. These proteins can recognize cellular stresses and infections.
 
Basically there are four main types of inflammasomes, which include NLRP1, NLRP3, NLRC4, and AIM2. Among these, NLRP3 is associated with RNA virus infection.
 
Interestingly the NRLP3 inflammasome consists of a sensor protein, adaptor protein, and effector protein. Previous research had shown that the NLRP3 protein contains three domains including the Pyrin domain (PYD), Nucleotide-binding domain, and Leucine-rich repeat domain. https://journals.asm.org/doi/full/10.1128/JVI.00996-19
 
It has been found that upon activation of the NLRP3 protein, the PYD interacts with the apoptosis-associated speck-like protein containing a caspase recruiting domain (ASC) and triggers the formation of ASC oligomer. This oligomer offers the platform for the activation of caspase-1, which catalyzes proteolytic processing of pro-interleukin (IL)-1β into mature IL-1β. https://www.nature.com/articles/nri3452
 
It has however been found that abundantly present IL-1β provokes the systemic inflammation responses, which are involved with various signaling pathways like the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase pathways.
 
Hence, a large number of cytokines, such as IL-6, tumor necrosis factor (TNF), interferon (IFN)-α, IFN-β, and transforming growth factor-β, are released, which can result in cytokine storms. Previous studies have revealed that SARS-CoV-2 infection elicits the production of inflammasomes that are linked with the severity of COVID-19.
 
Numerous studies have also reported that the E protein and the accessory protein ORF3a of SARS-CoV can activate NLRP3 inflammasome by altering the potassium (K+) ion permeability of the plasma membrane and by the production of mitochondrial reactive oxygen species. However, there remains a gap in research explaining the specific molecular pathway by which SARS-CoV-2 activates NLRP3 inflammasomes. https://www.sciencedirect.com/science/article/pii/S0042682215003566
 
https://www.frontiersin.org/articles/10.3389/fmicb.2019.00050/full
 
This new study findings have revealed the mechanism by which the SARS-CoV-2 N protein activates NLRP3 inflammasomes to induce hyperinflammation.
 
The study team also reports that in post-SARS-CoV-2 infection, the macrophages and dendritic cells (DCs) of the host trigger cytokines and chemokines. This observation was made by analyzing the GEO database (GSE155106).
 
The mouse model revealed that mechanistically, the SARS-CoV-2 N protein is responsible for intensifying lung injury and causing acute inflammation in mice by facilitating the activation of NLRP3 inflammasomes. The researchers have also found that N proteins directly interact with NLRP3 to promote the assembly of the NLRP3 inflammasome.
 
Past study by the same group of researchers on the Dengue and Zika viruses reported that, in the case of the Dengue virus, the M protein caused tissue damage and vascular leakage in mice by activating the NLRP3 inflammasome. In the case of the Zika virus, the NS5 protein promoted the entry of the virus into the brain.
 
It must be noted that the N protein of SARS-CoV-2 had been reported to play an important role in its replication process. The current study demonstrated that the SARS-CoV-2 N protein exists as the viral E protein that enters the cytoplasm and activates NLRP3 before viral assembly.
 
Furthermore, the study findings showed that the levels of IL-1β and IL-6 in the lungs and sera were increased by the lung-specific expression of N protein.
 
Interestingly however, the expressions of IL-1β and IL-6 were significantly reduced following the administration of inhibitors of NLRP3 and inhibitors of caspase-1.
 
The study team is extremely optimistic that inhibition of NLRP3 inflammasome can effectively reduce the “cytokine storm” and lung injury caused by COVID-19. In other words, they suggested that the NLRP3 inflammasome could be an alternative target for COVID-19 therapy.
 
Significantly, this study revealed that SARS-CoV-2 N-induced lung injury and cytokine production are repressed by specific NLRP3 inhibitors, and inhibitors of the caspase-1. Therefore, these two candidates can be potentially used as therapeutic agents for the prevention and treatment of COVID-19.

Thailand Medical news would also like to add that Melatonin is a very efficient inhibitor of NLRP3 inflammasomes and that we had covered this since May 2020. https://www.thailandmedical.news/news/breaking-covid-19-supplements-melatonin-helps-lessen-severity-risk-in-covid-19-patients-by-preventing-cytokine-storms
 
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